Pregabalin, which is chemically (S)-isomer of 3-(aminomethyl)-5-methylhexanoic acid, also called β-isobutyl-γ-aminobutyric acid or isobutyl-GABA, has the following chemical structure:

This compound is disclosed in EP641 330 B1 and marketed with the trade name Lyrica®. Pregabalin is useful as a therapeutic agent for the treatment of pain, epilepsy, convulsions, psychiatric disorders, attention deficit, hypersensitivity disorder, anxiety and mood disorders. It has been discovered that the anticonvulsant effect of pregabalin is dependent on its stereochemistry. The anticonvulsant effect of the racemic form of pregabalin is primarily attributable to the (S)-enantiomer, i.e., pregabalin. Pregabalin shows better anticonvulsant activity than its (R)-stereoisomer (Yuen et al., Bioorganic & Medicinal Chemistry Letters, 1994, 4, 823).
Several methods have been reported for the preparation of pregabalin. Typically racemic pregabalin is prepared and later resolved into (R) and (S) isomers using classical methods. First racemic pregabalin was described in Synthesis, 1989, 953. This method requires hazardous chemicals such as nitromethane and results in nitro intermediates which are unstable. U.S. Pat. No. 5,563,175 describes the synthesis of racemic pregabalin using an azide intermediate. U.S. Pat. No. 5,637,767 describes the synthesis of racemic pregabalin followed by resolution of S-isomer using mandelic acid. U.S. Pat. No. 6,046,353 describes the synthesis of racemic pregabalin through malonate salt. U.S. Pat. No. 5,616,793 describes the synthesis of racemic pregabalin through Hofmann rearrangement and resolution using chiral phenylethylamine.
In pregabalin, the carboxylic acid or amine moiety is not directly attached to an asymmetric carbon atom. Because of this, salt formation with a resolving agent is not selective and efficient. It requires several repeated crystallizations to obtain the desired enantiomeric purity. Further, the unwanted R-enantiomer cannot be efficiently racemised and recycled. It has to be ultimately discarded as waste adding to the production cost.
The direct synthesis of chirally pure S-pregabalin using Evan's chiral auxiliary (Scheme 1) is described in U.S. Pat. No. 5,599,973. The cost and recycling of the chiral auxiliary makes the process commercially unattractive.

Jacobsen's group reported a chiral synthesis of pregabalin using chiral aluminum salen catalyst and trimethylsilyl cyanide (J. Am. Chem. Soc., 2003, 125, 4442-4443). Although the method gives pregabalin with a high enantiomeric purity, it is not suitable for large scale industrial synthesis because of the high cost of reagents such as chiral aluminum salen catalyst and trimethylsilyl cyanide.
Another chiral synthesis of pregabalin is reported (A. Armstrong. et al. Synlett 2006, 10, 1589-1591), which uses samarium (III) isopropoxide as a catalyst. This method is also not suitable for industrial scale synthesis because of the expensive reagents.
EP 1 250 311 discloses the preparation of pregabalin using asymmetric hydrogenation of a cyano substituted olefin. It uses bisphosphine ligands such as (R, R)-Me-DUPHOS. The process also involves the use of carcinogenic acrylonitrile and highly toxic carbon monoxide under high pressure.
Thus, there is a need for the development of a cost effective enantioselective process which is suitable for industrial scale and free from some of the disadvantages mentioned in the above prior art.